A number of epidemiological studies, clinical intervention trials, and investigations in laboratory clearly support the protective role of selenium against the development of lung cancer. Selenium-enriched yeast, used as a nutritional supplement by humans, is a mixture of different forms of selenium compounds that reduces lung cancer incidence and mortality. The chemopreventive efficacy depends on 1) the chemical form of the selenium-containing compound and not the element per se; and 2) the dose and species employed. In our model assays the synthetic 1,4- phenylenebis(methylene)selenocyanate (pXSC) significantly inhibited lung tumors induced by the tobacco-specific lung carcinogen, 4- (methylnitrosamino)1-(3-pyridyl)1-butanone (NNK), in female A/J mice while the naturally occurring selenomethionine (SM) found in selenium- enriched had no female A/J mice while the naturally occurring selenomethionine (SM) found in selenium-enriched yeast had no effect in this animal model. In the present application, we propose four specific aims to obtain important information that is requisite for extending the utility of p-XSC from rodents to humans. In Specific Aim 1, we will determine the efficacy and biochemical basis for chemoprevention by comparing selenium-enriched yeast and one of its promising components, Se-methylselenocysteine (MSC), with PXSC in the NNK (chronically administered) A/J mouse model. Specific Aim 2 will probe the effect of various forms of selenium on the metabolism and DNA adduct formation in cultured explants of human tracheobronchial and peripheral lung. In Specific Aim 3, we will test a hypothesis that could lead to the identification of casual relationships by which selenium acts as a chemopreventive agent. Specifically on the basis of our results, we hypothesize that p-XSC inhibits lung tumorigenesis induced by NNK by inhibiting NF-kappaB, in part via covalent binding, thereby down- regulating COX-2 and LOX leading to apoptosis. However, an alternative mechanism by which p-XSC influences lkappaB degradation which, in turn, controls the translocation of NF-kappaB to the nucleus, will also be examined. These studies will be conducted, initially, in vitro using human lung carcinoma cell cultures and, later, in vivo using nude mice. In Specific Aim 2, we will determine the effect of various levels of selenium (as p-XSC and selenium-enriched yeast) and vitamins C and E as anti- oxidants that can inhibit cigarette smoke-induced oxidative damage in the lung of guinea pigs; and animal model that, to some extent, may mimic human biochemistry in that both species lack the ability to synthesize the anti-oxidant vitamin C. Collectively, the results of this Project will assess whether p-XSC is superior to MSC or selenium-enriched yeast in future clinical trials toward the chemoprevention of lung cancer in smokers and ex-smokers.